Method for preparing a coumarin compound, chromene compound, and method for preparing a chromene compound

ABSTRACT

Disclosed herein is a method for preparing a coumarin compound of formula (F), in which R 1 , R 2 , and R 3  are independently H, C 1 ˜C 7  alkoxy, C 1 ˜C 7  alkyl, phenoxy, benzyloxy, or a halogen atom; R 4  is an alkyl group; and Ar is an optionally substituted aryl group, 
                         
the method including: treating a chromene compound having the following formula (E)
 
                         
with an acid in the presence of water.
 
     A chromene compound of formula (E) and a method for preparing the chromene compound of formula (E) are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method for preparing a coumarin compound, a chromene compound, and a method for preparing the chromene compound.

2. Description of the Related Art

Coumarins and derivatives thereof have biological activities including anti-carcinogenic activity, fungicidal activity, anti-coagulant activity, etc. For example, coumarin-3-(N-aryl) sulfonamides (see the following formula (I)) exhibit anticancer activity (see N. S. Reddy et al., Bioorg. Med. Chem. Lett. 14 (2004) 4093-4097 and Coumarin-3 (N-aryl) carboxamides (see the following formula (II)) can be used to arrest growth of breast cancer cells (see N. S. Reddy at al., Bioorg. Med. Chem. 13 (2005), 3141-3147).

In formula (I), X¹ is 4-OCH₃, 3-OH, 4-F, or 4-Br; and Y¹ is 8-Br, 8-Cl, 8-OCH₃, 8-OC₂H₅; in formula (II), X² is H, 8-C₂H₅O, 6-Br, or 6-Cl; and Y² is 4-Br, 4-I, 4-Cl, 3-NO₂, or 3-NH₂.

Another coumarin derivative known in the art is 3-methoxymethyl coumarin, which can be prepared from 3-chloromethyl coumarin by the following reaction (see J. Org. Chem., 1960, 25 (10), pp 1713-1716):

Preparation of 3-methoxymethyl coumarin can also be conducted by the following reaction (see J. Org. Chem., 1962, 27 (2), pp 696-698),

However, trifluoroacetic acid is extremely corrosive and generates a poisonous gas in the reaction, and chloromethyl ether (ClCH₂OR) is a carcinogenic substance. Hence, the use of these compounds is likely to result in safety and health concerns.

Therefore, there is a need in the art to develop a process that is simple and safe in the preparation of a coumarin compound.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for preparing a coumarin compound, a chromene compound, and a method for preparing the chromene compound.

According to one aspect of this invention, there is provided a method for preparing a coumarin compound of formula (F), in which R¹, R², and R³ are independently H, C₁˜C₇ alkoxy, C₁˜C₇ alkyl, phenoxy, benzyloxy, or a halogen atom; R⁴ is an alkyl group; and Ar is an optionally substituted aryl group,

the method comprising: treating a chromene compound having the following formula (E)

with an acid in the presence of water.

According to another aspect of this invention, there is provided a chromene compound of formula (E):

wherein R¹, R², R³, R⁴, Ar have the same definitions as the aforesaid R¹, R², R³, R⁴, and Ar.

According to yet another aspect of this invention, there is provided a method for preparing the aforesaid chromene compound of formula (E), including reacting 3-cyanochromene of formula (B):

with R⁴OX and ArNH₂ in she presence of a solvent,

wherein, R¹, R², and R³ in formula (B), R⁴ in R⁴OX, and Ar in ArNH₂ have the same definitions as R¹, R², R³, R⁴, and Ar in formula (E); and X in R⁴OX is Na or K.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In this invention, the applicants endeavored to develop a simple and safe strategy for the synthesis of a coumarin compound.

Accordingly, this invention provides a chromene compound of formula (E):

wherein R¹, R², and R³ are independently H, C₁˜C₇ alkoxy, C₁˜C₇ alkyl, phenoxy, benzyloxy, or a halogen atom; R⁴ is an alkyl group; and Ar is an optionally substituted aryl group.

According to the preferred embodiments of this invention, R¹, R² and R³ are independently H, Cl, Br, benzyloxy (OBn), or methoxy (OMe).

Preferably, R⁴ is a C₁-C₄ alkyl group. In the examples of this invention, R⁴ is methyl (Me), ethyl (Et), i-propyl (i-Pr), or n-butyl (n-Bu).

Preferably, Ar is unsubstituted aryl, haloaryl alkylaryl, or alkoxyaryl. Examples of the unsubstituted aryl include, but are not limited to, phenyl (Ph) and naphthyl. Haloaryl is preferably halophenyl, and examples thereof include, but are not limited to, 4-fluoro-phenyl(4-FPh), 4-chloro-phenyl (4-ClPh), 4-bromo-phenyl (4-BrPh), 3-chloro-phenyl (3-ClPh), and 3-bromo-phenyl (3-BrPh). Alkylaryl is preferably alkylphenyl and examples thereof include, but are not limited to, 4-methyl-phenyl (4-MePh), 3-methyl-phenyl (3-MePh), 2-methyl-phenyl (2-MePh), 5-methyl-phenyl (5-MePh), and 6-methyl-phenyl (6-MePh). Alkoxyaryl is preferably alkoxyphenyl and examples thereof include, but are not limited to, 4-methoxy-phenyl (4-OMePh), 3-methoxy-phenyl (3-OMePh), 2-methoxy-phenyl (2-OMePh), 5-methoxy-phenyl (5-OMePh), and 6-methoxy-phenyl (6-OMePh). In the examples of this invention, Ar is phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, or 3-methoxy-phenyl.

The compound of formula (E) can be reacted with an acid in the presence of water so as to prepare a coumarin compound of formula (F):

wherein R¹, R², R³, and R⁴ in formula (F) have the same definitions as R¹, R², R³, and R⁴ in formula (E).

The acid and water used in the method for preparing the coumarin compound of formula (F) can provide H₃O⁺ to convert C═N—Ar into C═O. Examples of the acid include HCl, HBr, HI, CH₃CO₂H, and combinations thereof. In one preferred embodiment of this invention, the acid is HCl.

Preferably, the chromene compound of formula (E) is prepared by reacting 3-cyanochromene represented formula (B) with R⁴OX and ArNH₂ in the presence of a solvent,

wherein R¹, R², R³, R⁴ and Ar are as defined above; and X is Na or K.

Preferably, the solvent used for preparing the chromene compound of formula (E) is selected from the group consisting of R⁵OH and tetrahydrofuran (THF), wherein R⁵ is C₁˜C₄ alkyl.

Preferably, the reaction in the method for preparing the chromene compound of formula (E) is conducted under a reflux condition.

In the preferred embodiments of this invention, 3-cyanochromene of formula (B) is 3-cyano-2H-chromene (B₁), 6-chloro-3-cyano-2H-chromene (B₂), 6-bromo-3-cyano-2H-chromene (B₃), 7-benzyloxy-3-cyano-2H-chromene (B₄), 7-methoxy-3-cyano-2H-chromene (B₅, or 8-methoxy-3-cyano-2H-chromene (B₆).

3-cyanochromene of formula (B) may be prepared by conventional techniques. Preferably, 3-cyanochromene is prepared by reacting salicylaldehyde of formula (A) with acrylonitrile in the presence of a catalyst:

wherein R¹, R², and R³ are as defined above. In the preferred embodiments of this invention, salicylaldehyde of formula (A) is salicylaldehyde (A₁), 5-chlorosalicylaldehyde (A₂), 5-chlorosalicylaldehyde (A₃), 4-benzyloxysalicylaldehyde (A₄), 4-methyloxysalicylaldehyde (A₅), or 3-methyloxysalicylaldehyde (A₆).

Preferably, the catalyst is 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), trimethylamine, triethylamine, or triphenylphosphine (TPP).

In the preferred embodiments of this invention, the method for preparing the coumarin compound of formula (F) includes reactions in the following sequence:

It is noted that ArNH₂ (hereinafter referred to as compound (D)) formed as a byproduct of the last reaction can be recycled as the reagent for the reaction of preparing the chromene compound of formula (E). In the aforesaid series of reactions, the reagents and the materials thus used are safe and are commercially available. The coumarin compound of formula (F) can be easily and safely obtained by reacting the chromene compound of formula (E) with an acid.

The following examples are provided to illustrate the merits of the preferred embodiments of the invention, and should not be construed as limiting the scope of the invention.

EXAMPLES

The compounds prepared in the following Examples 1-36 were measured by structure identification using the following general procedures.

General Procedures:

-   1. The melting point was detected using a micro melting-point     apparatus (available from Yanaco company). -   2. ¹H-NMR and ¹³C-NMR spectra were detected using a Varian Unity-400     spectrometer. -   3. IR spectra were measured in a Perkin Elmer system 2000 FT-IR     spectrometer. -   4. Elemental analysis was recorded in an element analyzer (trade     name: Elementar vario EL III). -   5. Mass analysis was measured in a mass spectrometer (trade name:     Bruker APEX II).

Before the examples are illustrated, the species of the starting materials of compounds (A), the intermediate chromene compounds (B) and (E), the reagents (C) of R⁴ONa and (D) of ArNH², and the final products of coumarin compounds (F), as well as the substituted groups of R¹, R², R³, and R⁴ in Examples 1-36 are listed in Table 1 for the sake of clarity.

TABLE 1 Substituted groups of Ex Target Reactants compound (E) or (F) No. compound A B C D E R¹ R² R³ R⁴ Ar 1 E₁ A₁ B₁ C₁ D₁ — H H H Me Ph 2 E₂ C₂ D₁ — H H H Et Ph 3 E₃ C₂ D₂ — H H H Et 4-FPh 4 E₄ C₂ D₃ — H H H Et 4-ClPh 5 E₅ C₂ D₄ — H H H Et 4-BrPh 6 E₆ C₂ D₅ — H H H Et 4-MePh 7 E₇ C₂ D₆ — H H H Et 4-OMePh 8 E₈ C₂ D₇ — H H H Et 3-OMePh 9 E₉ C₃ D₁ — H H H i-Pr Ph 10 E₁₀ C₄ D₁ — H H H n-Bu Ph 11 E₁₁ A₂ B₂ C₂ D₁ — Cl H H Et Ph 12 E₁₂ C₂ D₂ — Cl H H Et 4-FPh 13 E₁₃ C₂ D₃ — Cl H H Et 4-ClPh 14 E₁₄ C₂ D₄ — Cl H H Et 4-BrPh 15 E₁₅ C₂ D₅ — Cl H H Et 4-MePh 16 E₁₆ C₂ D₆ — Cl H H Et 4-OMePh 17 E₁₇ C₂ D₇ — Cl H H Et 3-OMePh 18 E₁₈ A₃ B₃ C₂ D₁ — Br H H Et Ph 19 E₁₉ C₂ D₂ — Br H H Et 4-FPh 20 E₂₀ C₂ D₃ — Br H H Et 4-ClPh 21 E₂₁ C₂ D₄ — Br H H Et 4-BrPh 22 E₂₂ C₂ D₅ — Br H H Et 4-MePh 23 E₂₃ C₂ D₆ — Br H H Et 4-OMePh 24 E₂₄ C₂ D₇ — Br H H Et 3-OMePh 25 E₂₅ A₄ B₄ C₂ D₁ — H OBn H Et Ph 26 E₂₆ A₅ B₅ C₂ D₁ — H OMe H Et Ph 27 E₂₇ A₆ B₆ C₂ D₁ — H H OMe Et Ph 28 F₁ A₁ B₁ C₁ D₁ E₁ H H H Me Ph 29 F₂ A₁ B₁ C₂ D₁ E₂ H H H Et Ph 30 F₃ A₁ B₁ C₃ D₁ E₉ H H H i-Pr Ph 31 F₄ A₁ B₁ C₄ D₁ E₁₀ H H H n-Bu Ph 32 F₅ A₂ B₂ C₂ D₁ E₁₁ Cl H H Et Ph 33 F₆ A₃ B₃ C₂ D₁ E₁₈ Br H H Et Ph 34 F₇ A₄ B₄ C₂ D₁ E₂₅ H OBn H Et Ph 35 F₈ A₅ B₅ C₂ D₁ E₂₆ H OMe H Et Ph 36 F₉ A₆ B₆ C₂ D₁ E₂₇ H H OMe Et Ph

Preparation of 3-cyanochromene (B₁)˜(B₆)

Each of the compounds (B₁)˜(B₆) was prepared according to scheme I below by: mixing 20.0 mmol of a corresponding one of salicylaldehydes (A₁)˜(A₆) with 30.0 mmol of acrylonitrile to form a mixture; slowly adding a DABCO aqueous solution containing 22.0 mmol of DABCO and 30 mL, of water into the mixture to obtain a reaction solution; followed by refluxing the reaction solution under a nitrogen gas environment for 24 hrs.

The reaction product thus formed in the reaction solution was extracted using CH₂Cl₂, and was subsequently dried, filtered, concentrated, and purified by column chromatography with a suitable eluent so as to obtain a colorless crystal of 3-cyanochomene of formula (B).

Structure identification of 3-cyanochromenes [(B₁)˜(B₆)]

3-Cyano-2H-chromene (B₁): (2.51 g, 80%); m.p.: 44-45° C.; R_(f)=0.75 (ethyl acetate:n-hexane=1:6); IR (KBr cm⁻¹): 3059, 2851, 2212, 1623, 1482, 1458, 1233, 1211, 1148, 1034, 1020, 898, 759; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 4.81 (2H, d, J=1.6 Hz, H-2), 6.87 (1H, d, 8.0 Hz, ArH), 6.97 (1H, td, J=7.6, 1.2 Hz, ArH), 7.10 (1H, dd, J=8.0, 1.2 Hz, ArH), 7.17 (1H, br s, H-4), 7.27 (1H, m, ArH); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 64.2, 103.3, 116.4, 116.5, 120.0, 122.4, 128.4, 132.7, 138.8, 154.3; MS (EI) m/z: 157 (M⁺, 92%), 156 (100%).

6-Chloro-3-cyano-2H-chromene (B₂): (2.99 g, 78%); m.p.: 124-126° C.; R_(f)=0.76 (ethyl acetate:n-hexane=1:6); IR (KBr cm⁻¹): 3064, 2917, 2213, 1629, 1479, 1239, 1212, 1019, 914, 816; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 4.83 (2H, d, J=1.6 Hz, H-2), 6.82 (1H, d, J=8.6 Hz, H-8), 7.09 (1H, d, J=2.4 Hz, H-5), 7.11 (1H, br s, H-4), 7.22 (1H, dd, J=8.6, 2.4 Hz, H-7); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 64.4, 104.8, 115.9, 118.0, 121.1, 127.3, 127.7, 132.3, 137.6, 152.7; MS (EI) m/z: 193 ([M+2]⁺, 29%), 191 (M⁺, 91%), 190 (87%), 156 (100%).

6-Bromo-3-cyano-2H-chromene (B₃): (3.54 g, 75%); m.p.: 132-133° C.; R_(f)=0.77 (ethyl acetate:n-hexane=1:6); IR (KBr cm⁻¹): 3063, 2878, 2211, 1627, 1476, 1236, 1211, 1018, 915, 815; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 4.83 (2H, d, J=1.2 Hz, H-2), 6.76 (1H, d, J=8.4 Hz, H-8), 7.10 (1H, br s, H-4), 7.23 (1H, d, J=2.4 Hz, H-5), 7.36 (1H, dd, J=8.4, 2.4 Hz, H-7); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 64.4, 104.7, 114.4, 115.9, 118.4, 121.5, 130.6, 135.1, 137.4, 153.2; MS (EI) m/z: 237 ([M+2]⁺, 41%), 235 (M⁺, 49%), 157 (75%), 156 (100%).

7-Benzyloxy-3-cyano-2H-chromene (B₄): (3.79 g, 72%); m.p.: 108-109° C.; R_(f)=0.35 (ethyl acetate:n-hexane=1:9); IR (KBr cm⁻¹): 3033, 2957, 2206, 1615, 1561, 1271, 1166, 851, 737; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 4.77 (2H, d, J=1.2 Hz, H-2), 5.05 (2H, s, OCH₂Ph), 6.49 (1H, d, J=2.4 Hz, H-8), 6.59, dd, J=8.6, 2.4 Hz, H-6), 7.01 (1H, d, J=8.6 Hz, H-5), 7.12 (1H, m, H-4), 7.32-7.41 (5H, m, ArH); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 64.4, 70.2, 99.5, 102.8, 109.6, 113.6, 116.9, 127.4, 128.2, 128.7, 129.6, 136.0, 138.7, 155.9, 162.5; MS (EI) m/z: 263 (M⁺, 7%), 91 (100%); Anal. calcd for C₁₇H₁₃NO₂ (263.29): C, (77.55); H, (4.98); N, (5.32). found. C, (77.57); H, (5.02); N, (5.20).

7-Methoxy-3-cyano-2H-chromene (B₅): (2.77 g, 74%); m.p.: 97-99° C.; R_(f)=0.30 (ethyl acetate:n-hexane=1:9); IR (KBr cm⁻¹): 3065, 2964, 2205, 1618, 1564, 1435, 1279, 868, 805; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 3.78 (3H, s, OCH₃), 4.76 (2H, d, J=0.8 Hz, H-2), 6.40 (1H, d, J=2.4 Hz, H-8), 6.50, (1H, J=8.4, 2.4 Hz, H-6), 7.00 (1H d, J=8.4 Hz, H-5), 7.11 (1H, br s, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 55.5, 64.4, 99.3, 101.8, 108.9, 113.4, 116.9, 129.5, 138.7, 155.9, 163.4; MS (EI) m/z: 187 (M⁺, 80%), 186 (100%).

8-Methoxy-3-cyano-2H-chromene (B₆): (2.85 g, 76%); m.p.: 105-106° C.; R_(f)=0.58 (ethyl acetate:n-hexane=1:3); IR (KBr cm⁻¹): 3056, 2956, 2838, 2210, 1625, 1606, 1575, 1482, 1336, 1274, 1221, 1098, 1021, 733; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 3.88 (3H, s, OCH₃), 4.87 (2H, d, J=1.2 Hz, H-2), 6.75 (1H, dd, J=5.6, 3.6 Hz, ArH), 6.93, (1H, J=3.6 Hz, ArH), 6.93 (1H, d, J=5.6 Hz, ArH), 7.18 (1H, t, J=1.2 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 56.1, 64.5, 103.4, 115.2, 116.3, 120.2, 120.7, 122.2, 138.8, 143.2, 148.0; MS (EI) m/z: 187 (M⁺, 100%), 186 (39%), 144 (69%), 116 (40%), 89 (32%).

Examples 1˜27 Preparation of the Chromene Compounds (E₁)˜(E₂₇)

Each of the chromene compounds (E₁)˜(E₂₇) of Examples 1˜27 was prepared according to scheme II below by: dissolving 5.0 mmol of a corresponding one of 3-cyanochromenes (B₁)˜(B₆) in THF to form a solution; mixing 7.5 mmol of a corresponding one of the compounds (C₁)˜(C₄) and 10.0 mmol of a corresponding one of the compounds (D₁)˜(D₇) with the above solution to form a reaction solution; followed by refluxing the reaction solution under a nitrogen gas environment for 1˜3 hrs.

The reaction product thus formed was separated from the reaction solution, and was then purified by column chromatography with a suitable eluent so as to obtain a yellow crystal of intermediate chromene compound of formula (E).

Structure Identification of the Intermediate Chromene Compounds [(E₁)˜(E₂₇)]

3-Methoxymethyl-2-phenylimino-2H-chromene (E₁): (0.86 g, 65%); m.p.: 64-65° C.; R_(f)=0.512 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 3.53 (s, 3H, CH₂OCH₃), 4.40 (d, J=1.6 Hz, 2H, CH₂OCH₃), 7.00 (H, J=8.0 Hz, 1H, ArH), 7.06-7.12 (m, 2H, RC═NArH), 1.17 (dt, J=6.4, 1.2 Hz, 2H, RC═NArH), 7.25 (td, J=7.2, 1.6 Hz, 1H, ArH), 7.29 (dd, 7.6, 1.6 Hz, 1H, ArH) 7.32-7.36 (m, 3H, ArH, ArCH═C, RC═NArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 58.98, 69.57, 115.33, 119.79, 122.87, 123.58, 123.69, 127.10, 128.54, 128.90, 129.63, 129.68, 145.95, 147.74, 152.23; IR (KBr cm⁻¹): 2936, 2869, 2363, 1644, 1585, 1487, 1451, 1403, 1225, 1180, 1115, 1058, 761, 705; EI-MS (70 eV) m/z: 265 (M⁺, 10%), 251 (18%), 250 (100%), 235 (27%), 234 (21%), 233 (11%), 232 (22%), 222 (21%); Anal. calcd for C₁₇H₁₅NO₂: N, 5.28; C, 76.96; H, 5.70. found: N, 5.22; C, 76.93; H, 5.68.

3-Ethoxymethyl-2-phenylimino-2H-chromene (E₂): (1.1 g, 79%); m.p.: 71˜72° C.; R_(f)=0.564 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.37 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.74 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.53 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 7.04 (dd, J=8.0, 0.4 Hz, 1H, ArH), 7.11-7.16 (m, 2H, RC═NArH), 7.21-7.24 (m, 2H, RC═NArH), 7.29 (td, J=8.0, 1.2 Hz, 1H, ArH), 7.34-7.41 (m, 3H, ArH, RC═NArH), 7.42 (t, J=1.6 Hz, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.58, 67.06, 67.84, 115.69, 120.22, 123.21, 123.92, 124.02, 127.46, 128.90, 129.62, 129.93, 130.02, 146.36, 148.22, 152.57; IR (KBr cm⁻¹): 2978, 2861, 2362, 1640, 1583, 1486, 1449, 1386, 1227, 1182, 1116, 1064, 758, 703; EI-MS (70 eV) m/z: 279 (M⁺, 0.3%), 251 (17%), 250 (100%), 236 (49%), 235 (58%), 233 (47%), 231 (17%), 221 (12%); Anal. calcd for C₁₈H₁₇NO₂: N, 5.01; C, 77.40; H, 6.13. found: N, 4.82; C, 77.46; H, 6.21.

3-Ethoxymethyl-2-(4-fluorophenyl)imino-2H-chromene (E₃): (0.94 g, 63%); m.p.; 84˜86° C., R_(f)=0.538 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.35 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 3.72 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.49 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 7.02 (dd, J=8.0, 0.8 Hz, 1H, ArH), 7.04-7.07 (m, 2H, RC═NArH), 7.13 (td, J=7.6, 1.2 Hz, 1H, ArH), 7.18-7.22 (m, 2H, RC═NArH), 7.30 (td, 7.6, 1.6 Hz, 1H, ArH), 7.34 (td, J=7.6, 1.2 Hz, 1H, ArH), 7.40 (t, J=1.2 Hz, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 66.74, 67.47, 115.07, 115.30, 119.89, 123.72, 124.40, 124.47, 127.20, 129.24, 129.67, 129.77, 152.16, 158.21, 160.62; IR (KBr cm⁻¹): 2975, 2861, 2365, 1642, 1589, 1502, 1227, 1185, 1155, 1111, 1063, 844, 758; EI-MS (70 eV) m/z: 299 ([M+2]⁺, 0.06%), 297 (M⁺, 0.3%), 269 (17%), 268 (100%), 255 (17%), 254 (30%), 253 (71%), 252 (16%), 251 (32%), 240 (20%); Anal. calcd for C₁₈H₁₆FNO₂: N, 4.71; C, 72.71; H, 5.42. found: N, 4.70; C, 72.77; H, 5.45.

3-Ethoxymethyl-2-(4-chlorophenyl)imino-2H-chromene (E₄): (1.00 g, 64%); m.p.: 84˜86° C., R_(f)=0.564 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.35 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.71 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.49 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 7.03 (d, J=8.4 Hz, 1H, ArH), 7.12-7.16 (m, 2H, RC═NArH), 7.20 (dd, J=6.8, 1.6 Hz, 1H, ArH), 7.26-7.33 (m, 2H, RC═NArH), 7.35 (dd, J=7.6, 1.2 Hz, 1H, ArH), 7.38 (d, J=8.0 Hz, 1H, ArH), 7.42 (t, J=1.6 Hz, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 66.75, 67.42, 115.30, 119.83, 123.79, 124.35, 127.30, 128.60, 128.78, 129.10, 129.77, 130.10, 144.59, 152.11, 162.89; IR (KBr cm⁻¹): 2971, 2859, 2361, 1641, 1593, 1483, 1448, 1224, 1182, 1117, 1057, 837, 760; EI-MS (70 eV) m/z: 315 ([M+2]⁺, 0.2%), 313 (M⁺, 0.9%), 286 (34%), 285 (23%), 284 (100%), 271 (31%), 270 (29%), 269 (94%), 268 (50%), 256 (20%), 207 (22%); Anal. calcd for C₁₈H₁₆ClNO₂: N, 4.46; C, 68.90; H, 5.14. found: N, 4.31; C, 68.91; H, 5.30.

3-Ethoxymethyl-2-(4-bromophenyl)imino-2H-chromene (E₅): (1.16 g, 65%); m.p.: 73˜74° C.; Rf=0.590 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.34 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 3.71 (q, J=7.2 Hz, 2H, CH₂OCH₂CH₃), 4.48 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 7.04 (d, J=8.4 Hz, 1H, ArH), 7.08 (dt, J=8.8, 2.8 Hz, 2H, RC═NArH), 7.15 (td, J=7.6, 1.2 Hz, 1H, ArH), 7.31 (td, J=8.0, 1.6 Hz, 1H, ArH), 7.36 (dd, J==7.6, 1.6 Hz, 1H, ArH), 7.43 (t, J=2.0 Hz, 1H, ArCH═C), 7.45 (td, J=8.8, 2.4 Hz, 1H, RC═NArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.25, 66.79, 67.43, 115.36, 116.60, 119.86, 123.86, 124.76, 127.28, 129.10, 129.85, 130.25, 131.59, 145.11, 148.50, 152.14; IR (KBr cm⁻¹): 2973, 2878, 2369, 1637, 1597, 1477, 1218, 1177, 1108, 1061, 1005, 835, 758; EI-MS (70 eV) 359 ([M+2]⁺, 0.35%), 357 (M⁺, 0.26%), 330 (73%), 328 (68%), 315 (79%), 314 (63%), 313 (62), 233 (81%), 231 (100%), 220 (66%); Anal. calcd for C₁₈H₁₆BrNO₂: N, 3.91; C, 60.35; H, 4.50. found: N, 3.81; C, 60.37; H, 4.51.

3-Ethoxymethyl-2-(4-ethylphenyl)imino-2H-chromene (E₆): (0.98 g, 67%); m.p.: 104˜105° C.; R_(f)=0.564 (ethyl acetate:n-hexane=1:7) ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.37 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 2.39 (s, 3H, RC═NArCH₃) 3.74 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 53 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 7.06 (d, J=8.0 Hz, 1H, ArH), 7.13 (td, J=7.6, 1.2 Hz, 1H, ArH) 7.16-7.21 (m, 4H, RC═NArH), 7.29 (td, J=8.0, 1.6 Hz, 1H, ArH), 7.32 dd, J=7.6, 1.6 Hz, 1H, ArH), 7.39 (t, J=1.6 Hz 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.58, 21.30, 67.04, 67.88, 115.64, 120.28, 123.31, 123.85, 127.42, 129.50, 129.66, 129.79, 129.84, 133.55, 143.56, 147.96, 152.63; IR (KBr cm⁻¹): 2971, 2870, 2361, 1651, 1589, 1477, 1415, 1382, 1228, 1178, 1122, 1061, 902, 809, 766, 736, 691; EI-MS (70 eV) m/z: 293 (M⁺, 0.6%), 265 (19%), 264 (100%), 245 (87%), 249 (21%), 248 (49%), 246 (16%), 236 (10%); Anal. calcd for C₁₈H₁₆CH₃NO₂: N, 4.77; C, 77.79; H, 6.53. found: N, 4.67; C, 77.80; H, 6.51.

3-Ethoxymethyl-2-(4-methoxyphenyl)imino-2H-chromene (E₇): (1.00 g, 65%); m.p.: 78˜79° C., R_(f)=0.385 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.35 (t, J=7.2 Hz, CH₂OCH₂CH₃), 3.72 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 3.83 (s, 3H, RC═NArOCH₃), 4.50 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.91 (dt, J=9.2, 3.2 Hz, 2H, RC═NArH), 7.07 (d, J=8.0 Hz, 1H, ArH), 7.11 (td, J=7.6, 1.2 Hz, 1H, ArH), 7.28 (dt, J=9.2, 3.2 Hz, 2H, RC═NArH), 7.31-7.34 (m, 2H, ArH), 7.35 (t, J=1.6 Hz, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.56, 55.64, 67.01, 67.89, 114.08, 115.57, 120.33, 123.84, 127.96, 127.40, 129.34, 129.79, 129.90, 139.12, 147.57, 152.61, 156.52; IR (KBr cm⁻¹): 2969, 2866, 2363, 1648, 1599, 1507, 1446, 1244, 1178, 1113, 1061, 1032, 832, 745; EI-MS (70 eV) m/z: 309 (M⁺, 5%), 281(150), 280 (75%), 266 (25%), 265 (100%), 264 (15%), 262 (16%), 250 (22%); Anal. calcd for C₁₉H₁₉NO₃: N, 4.53; C, 73.77; H, 6.19. found: N, 4.44; C, 73.78; H, 6.23.

3-Ethoxymethyl-2-(3-methoxyphenyl)imino-2H-chromene (E₈): (0.97 g, 63%); R_(f)=0.410 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.34 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.71 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 3.82 (s, 3H, RC═NArOCH₃), 4.50 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.68 (dt, J=8.4, 0.8 Hz, 1H, RC═NArH), 6.75 (t, J=2.0 Hz, 1H, RC═NArH), 6.79 (dt, J=8.0, 0.8 Hz, 1H, RC═NArH), 7.04 (d, J=8.4 Hz, 1H, ArH), 7.12 (td, J=7.6, 1.2 Hz, 1H, ArH), 7.25 (t, J=8.0 Hz, 1H, RC═NArH), 7.29 (td, J=8.0, 1.6 Hz, 1H, ArH), 7.34 (dd, J=7.6, 1.6 Hz, 1H, ArH), 7.40 (t, J=1.6 Hz, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.24, 55.18, 66.76, 67.51, 108.31, 109.71, 115.33, 115.43, 119.90, 123.66, 127.18, 129.25, 129.67, 129.85, 147.36, 152.29, 159.99; EI-MS (70 eV) m/z: 309 (M⁺, 0.5%), 281 (16%), 280 (83%), 266 (31%), 265 (100%), 264 (41%), 263 (22%), 262 (18%); HRMS (ESI, m/z): Calcd. for C₁₉H₁₉NO₃: 309.3591; found: 309.3590.

3-isopropoxymethyl-2-phenylimino-2H-chromene (E₉): (1.2.0 q, 82%); m.p.: 107˜108° C., R_(f)=0.605 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.30 (d, J=6.0 Hz, 6H, CH₂OCH(CH₃)₂), 3.77-3.84 (m, 1H, CH₂OCH(CH₃)₂), 4.50 (d, J=2.0 Hz, 2H, CH₂OCH(CH₃)₂), 7.01 (d, J=8.0 Hz, 1H, ArH), 7.08-7.13 (m, 2H, RC═NArH), 7.19 (dt, J=6.4, 0.8 Hz, 2H, RC═NArH), 7.27 (td, J=7.6, 1.6 Hz, 1H, ArH), 7.32-7.37 (m, 3H, ArH, RC═NArH), 7.41 (t, J=1.6, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 22.24, 65.25, 72.25, 115.37, 120.00, 122.87, 123.59, 123.67, 127.15, 128.60, 129.54, 12974, 129.83, 146.12, 148.03, 152.25; IR (KBr cm⁻¹): 2964, 2873, 2364, 1647, 1590, 1484, 1451, 1370, 1216, 1179, 1124, 1039, 763, 691; EI-MS (70 eV) m/z: 293 (M⁺, 0.7%), 251 (19%), 250 (100%), 236 (16%), 235 (85%), 234 (64%), 233 (20%), 232 (23%), 222 (23%); Anal. calcd for C₁₉H₁₉NO₂: N, 4.77; C, 77.79; H, 6.53. found: N, 4.68; C, 77.87; H, 6.57.

3-Butoxymethyl-2-phenylimino-2H-chromene (E₁₀): (1.32 g, 86%); m.p.: 86˜88° C.; R_(f)=0.651 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.00 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₂CH₂CH₃), 1.44-1.54 (m, 2H, CH₂OCH₂CH₂CH₂CH₃), 1.68-1.75 (m, 2H, CH₂OCH₂CH₂CH₂CH₃), 3.58 (t, J=6.4 Hz, 2H, CH₂OCH₂CH₂CH₂CH₃), 4.51 (d, J=2.0 Hz, 2H, CH₂O(CH₂)₃CH₃), 7.04 (d, J=8.4 Hz, 1H, ArH), 7.10-7.15 (m, 2H, RC═NArH), 7.21 (dt, J=6.8, 1.6 Hz, 2H, RC═NArH), 7.29 (td, J=8.0, 1.6 Hz, 1H, ArH), 7.34-7.39 (m, 3H, ArH, RC═NArH), 7.40 (t, J=1.6, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 13.95, 19.40, 31.84, 67.71, 71.23, 115.39, 119.95, 122.88, 123.60, 123.69, 127.16, 128.59, 129.45, 129.60, 129.68, 146.09, 147.92, 152.29; IR (KBr cm⁻¹): 2955, 2864, 2367, 1646, 1590, 1482, 1450, 1381, 1216, 1180, 1113, 1071, 759, 689; EI-MS (70 eV) m/z: 307 (M⁺, 0.5%), 251 (18%), 250 (100%), 237 (16%), 235 (84%), 234 (72%), 233 (16%), 232 (21%), 222 (16%); Anal. calcd for C₂₀H₂₁NO₂: N, 4.56; C, 78.15; H, 6.89. found: N, 4.46; C, 78.14; H, 6.87.

6-Chloro-3-ethoxymethyl-2-phenylimino-2H-chromene (E₁₁): (1.06 g, 68%); m.p.: 58˜59° C., R_(f)=0.465 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.49 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.95 (d, J=8.8 Hz, 1H, ArH), 7.11 (tt, J=7.6, 0.8 Hz, 1H, RC═NArH), 7.13 (dt, J=7.6, 1.2 Hz, 2H, RC═NArH), 7.22 (dd, J=8.8, 2.8 Hz, 1H, ArH), 7.31-7.38 (m, 4H, ArH, ArCH═C, RC═NArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.24, 66.83, 67.43, 116.14, 121.19, 122.81, 123.97, 126.48, 128.43, 128.64, 129.39, 130.80, 145.68, 147.17, 150.70; IR (KBr cm⁻¹): 2972, 2871, 2358, 1651, 1590, 1479, 1418, 1382, 1226, 1178, 1121, 1060, 902, 810, 766, 736, 690; ET-MS (70 eV) m/z: 315 ([M+2]⁺, 0.5%), 313 (M⁺, 0.4%), 286 (34%), 285 (23%), 284 (100%) 271 (79%), 270 (37%), 269 (53%), 268 (39%); Anal. calcd for C₁₈H₁₆ClNO₂: N, 4.46; C, 68.90; H, 5.14. found: N, 4.37; C, 68.89; H, 5.13.

6-Chloro-3-ethoxymethyl-2-(4-fluorophenyl)imino-2H-chromene (E₁₂): (1.06 g, 64%); m.p.: 36-137° C., R_(f)=0.419 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 3.70 (g, J=7.2 Hz, 2H, CH₂OCH₂CH₃), 4.47 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.98 (d, J=8.8 Hz, 1H, ArH) 7.01-7.05 (m, 2H, RC═NArH), 7.16-7.19 (m, 2H, RC═NArH), 7.25 (dd, J=8.8, 2.4 Hz, 1H, ArH), 7.32 (t, J=2.0 Hz, 1H, ArCH═C), 7.33 (d, J=2.4 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 66.86, 67.41, 1145.18, 115.40, 116.68, 121.20, 124.40, 124.48, 126.58, 128.56, 129.48, 130.78, 150.63, 158.40, 160.81; IR (KBr cm⁻¹): 2970, 2866, 2367, 1653, 1500, 1419, 1182, 1120, 1064, 907, 816; ET-MS (70 eV) m/z: 333 [M+2]⁺, 0.05%), 331 (M⁺, 0.5%), 304 (31%), 303 (20%), 302 (91%), 290 (24%), 288 (100%), 286 (45%), 274 (14%); Anal. calcd for C₁₈H₁₅ClFNO₂: N, 4.22; C, 65.16; H, 4.56. found: N, 4.15; C, 65.18; H, 4.66.

6-Chloro-3-ethoxymethyl-2-(4-chlorophenyl)imino-2H-chromene (E₁₃): (1.15 g, 66%); m.p.: 126˜128° C., R_(f)=0.488 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=7.6 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.47 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.98 (d, J=8.8 Hz, 1H, ArH), 7.11 (dt, J=9.6, 2.8 Hz, 2H, RC═NArH), 7.24-7.27 (m, 2H, RC═NArH), 7.30 (dd, J=8.8, 2.4 Hz, 1H, ArH), 7.32 (d, J=2.4 Hz, 1H, ArH), 7.33 (t, J=1.6 Hz, 1H, ArCH═C); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.22, 66.87, 67.36, 116.71, 117.94, 121.15, 124.29, 126.61, 128.71, 128.89, 129.58, 130.64, 130.92, 136.68, 150.60, 159.83; IR (KBr cm⁻¹): 2972, 2866, 2366, 1647, 1480, 1418, 1258, 1181, 1121, 1063, 1004, 892, 812; EI-MS (70 eV) m/z: 349 ([M+2]⁺, 0.14%), 347 (M⁺, 0.4%) 320 (70%), 319 (100%), 306 (59%), 305 (53%), 304 (91%), 302 (47%), 207 (37%); Anal. calcd for C₁₈H₁₅Cl₂NO₂: N, 4.02; C, 62.08; H, 4.34. found: N, 4.01; C, 62.11; H, 38.

6-Chloro-3-ethoxymethyl-2-(4-bromophenyl)imino-2H-chromene (E₁₄): (1.23 g, 63%); m.p.: 119˜121° C.; R_(f)=0.465 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.46 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.97 (d, J=8.8 Hz, 1H, ArH), 7.05 (dt, J=8.8, 2.0 Hz, 2H, RC═NArH), 7.25 (dd, J=8.4, 2.4 Hz, 1H, ArH), 7.33-7.34 (m, 2H, ArH, ArCH═C), 7.45 (dt, J=8.4, 2.0 Hz, 2H, RC═NArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 66.87, 67.34, 116.70, 116.89, 121.14, 124.68, 126.60, 128.92, 129.58, 130.63, 131.66, 144.78, 147.69, 150.58; IR (KBr cm⁻¹): 2970, 2866, 2367, 1647, 1590, 1500, 1470, 1418, 1381, 1230, 1179, 1118, 1060, 900, 80; EI-MS (70 eV) m/z: 393 ([M+2]⁺, 0.14%), 391 (M⁺, 0.19%), 366 (26%), 364 (100%), 362 (75%), 350 (32%), 349 (94%), 348 (69%), 347 (80%); Anal. calcd for C₁₈H₁₅BrClNO₂: N, 3.57; C, 55.06; H, 3.85. found: N, 3.49; C, 55.08; H, 3.89.

6-Chloro-3-ethoxymethyl-2-(4-methylphenyl)imino-2H-chromene (E₁₅): (1.10 g, 67%); m.p.: 76˜77° C., R_(f)=465 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 2.35 (s, 3H, RC═NArCH₃), 3.70 (q, J=7.2 Hz, 2H, CH₂OCH₂CH₃), 4.48 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.97 (d, J=8.8 Hz, 1H, ArH), 7.10-7.16 (m, 4H, RC═NArH), 7.22 (dd, J=8.8, 2.4 Hz 1H, ArH), 7.29 (t, J=2.0 Hz, 1H, ArCH═C), 7.30 (d, J=2.0 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.24, 21.00, 66.82, 67.49, 116.70, 121.28, 122.94, 126.46, 128.13, 128.59, 129.24, 129.30, 130.98, 133.61, 142.87, 146.94, 150.78; IR (KBr cm⁻¹): 2963, 2858, 2367, 1644, 1478, 1414, 1381, 1265, 1220, 1181, 1122, 1064, 900, 810; EI-MS (70 eV) m/z: 329 ([M+2]⁺, 0.48%), 327 (M⁺, 0.72%), 300 (33%), 299 (22%) 298 (100%), 286 (30%), 285 (67%), 284 (98%), 282 (55%); Anal. calcd for C₁₉H₁₈ClNO₂: N, 4.27; C, 69.62; H, 5.53. found: N, 4.25; C, 69.58; H, 5.54.

6-Chloro-3-ethoxymethyl-2-(4-methoxyphenyl)imino-2H-chromene (E₁₆): (1.10 q, 64%); m.p.: 136˜138° C., R_(f)=0.302 (ethyl acetate:n hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 3.83 (s, 3H, RC═NArOCH₃), 4.48 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.90 (dt, 8.8, 2.4 Hz, 2H, RC═NArH), 7.01 (d, J=8.4 Hz, ArH), 7.22-7.26 (m, 3H, ArH, RC═NArH), 7.27 (t, J=2.0 Hz, 1H, ArCH═C), 7.31 (d, J=2.4 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.25, 55.42, 66.82, 67.53, 113.87, 116.65, 121.38, 124.71, 126.47, 127.82, 128.60, 129.27, 131.13, 138.45, 146.55, 150.80, 156.48; IR (KBr cm⁻¹): 2977, 2861, 2365, 1643, 1597, 1507, 1418, 1242, 1179, 1133, 1062, 1023, 816; EI-MS (70 eV) m/z: 345 ([M+2]⁺, 3%), 343 (M⁺, 9%), 316 (34%), 315 (23%), 314 (96%), 302 (35%), 300 (49%), 299 (100%), 298 (34%), 284 (23%); Anal. calcd for C₁₉H₁₈ClNO₃: N, 4.07; C, 66.38; H, 5.28. found: N, 4.02; C, 66.33; H, 5.27.

6-Chloro-3-ethoxymethyl-2-(3-methoxyphenyl)imino-2H-chromene (E₁₇): (1.13 g, 66%); m.p.: 96.5˜97.5° C., R_(f)=0.326 (ethyl acetate:n-hexane=1:1); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.34 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 3.71 (q, J=7.2 Hz, 2H, CH₂OCH₂CH₃), 3.82 (s, 3H, RC═NArOCH₃), 4.49 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.69 (dt, J=8.4, 0.8 Hz, 1H, RC═NArH), 6.74 (t, J=2.0 Hz, 1H, RC═NArH), 6.78 (dt, J=8.0, 0.8 Hz, 1H, RC═NArH), 6.98 (d, J=8.4 Hz, 1H, ArH), 7.21 (dd, J=8.0, 2.4 Hz, 1H, ArH) 7.25 (t, J=8.0 Hz, 1H, RC═NArH), 7.31 (m, 2H, ArCH═C, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.20, 55.16, 66.79, 67.38, 108.33, 109.80, 115.20, 116.73, 121.12, 126.46, 128.51, 129.27, 129.36, 130.72, 146.94, 150.67, 159.98; IR (KBr cm⁻¹): 2970, 2862, 2364, 1650, 1584, 1480, 1268, 1231, 1180, 1123, 1065, 908, 853, 807, 781; EI-MS (70 eV) m/z: 345 ([M+2]⁺, 0.7%), 343 (M⁺, 0.24%), 316 (18%), 314 (55%), 302 (13%), 301.5 (16%), 300 (100%), 298 (33%), 297 (15%), 296 (15%); Anal. calcd for C₁₉H₁₈ClNO₃: N, 4.07; C, 66.38; H, 5.28. found: N, 4.00; C, 66.40; H, 5.26.

6-Bromo-3-ethoxymethyl-2-phenylimino-2H-chromene (E₁₈): (1.16 g, 64%) m.p.: 78˜80° C., R_(f)=0.452 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=7.2, Hz, 2H, CH₂OCH₂CH₃), 4.49 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.90 (d, J=8.8 Hz, 1H, ArH), 7.08 (tt, J=8.8, 0.8 Hz, 1H, RC═NArH), 7.17 (dt, J=8.4, 2.4 Hz, 2H, RC═NArH), 7.30 (t, J=2.0, 1H, ArCH═C) 7.32-7.37 (m, 3H, ArH, RC═NArH), 7.46 (d, J=2.4 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 66.82, 67.42, 115.99, 117.09, 121.69, 122.81, 123.98, 128.33, 128.64, 129.47, 130.79, 132.24, 145.62, 147.09, 151.19; IR (KBr cm⁻¹): 2971, 2870, 2361, 1651, 1589, 1415, 1382, 1228, 1178, 1122, 1061, 902, 809, 766, 736, 691; EI-MS (70 eV) m/z: 359 ([M+2]⁺, 1.4%), 357 (M⁺, 1.4%), 330 (98%), 329 (100%), 316 (79%), 315 (68%), 314 (90%), 312 (55%); Anal. calcd for C₁₈H₁₆BrNO₂: N, 3.91; C, 60.35; H, 4.50. found: N, 3.68; C, 60.19; H, 4.78.

6-Bromo-3-ethoxymethyl-2-(4-fluorophenyl)imino-2H-chromene (E₁₉): (1.22 g, 65%); m.p.: 153˜154° C.; R_(f)=0.429 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=7.2, Hz, 2H, CH₂OCH₂CH₃), 4.47 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.92 (d, J=8.8 Hz, 1H, ArH), 7.01-7.06 (m, 2H, RC═NArH), 7.15-7.19 (m, 2H, RC═NArH), 7.31 (t, J=1.6, 1H, ArCH═C), 7.39 (dd, J=8.8, 2.4 Hz, 1H, ArH), 7.47 (d, J=2.4 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 66.84, 67.40, 115.17, 115.40, 116.14, 117.02, 121.70, 124.40, 128.39, 129.55, 130.77, 132.31, 151.11, 158.39, 160.80; IR (KBr cm⁻¹): 2972, 2866, 2363, 1650, 1591, 1499, 1414, 1383, 1183, 1122, 1062, 908, 818, 781; EI-MS (70 eV) m/z: 377 ([M+2]⁺, 0.14%), 375 (M⁺, 0.03%), 348 (63%), 347 (60%), 334 (86%), 332 (100%), 238 (64%), 237 (49%); Anal. calcd for C₁₈H₁₅BrFNO₂: N, 3.72; C, 57.46; H, 4.02. found: N, 3.65; C, 57.56; H, 4.05.

6-Bromo-3-ethoxymethyl-2-(4-chlorophenyl)imino-2H-chromene (E₂₀): (1.27 g, 62%); m.p.: 144˜145° C., R_(f)=0.476 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.47 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.92 (d, J=8.8 Hz, 1H, ArH) 7.11 (dt, J=8.8, 3.2 Hz, 2H, RC═NArH), 7.30 (dt, J===8.8, 2.8 Hz, 2H, RC═NArH), 7.33 (t, J=2.0, 1H, ArCH═C), 7.39 (dt, J=8.8, 2.4 Hz, 1H, ArH), 7.48 (d, J=2.0 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.22, 66.86, 67.34, 116.23, 117.05, 121.64, 124.29, 128.71, 128.74, 129.13, 129.58, 130.64, 132.42, 144.22, 147.61, 151.07; IR (KBr cm⁻¹): 2971, 2863, 2361, 1646, 1599, 1477, 1382, 1225, 1180, 1122, 1063, 904, 811; EI-MS (70 eV) m/z: 393 ([M+2]⁺, 0.02%), 391 (M⁺, 0.02%), 364 (100%), 363 (81%), 351 (35%), 350 (90%), 349 (60%), 348 (73%), 346 (33%); Anal. calcd for C₁₈H₁₅BrClNO₂: N, 3.57; C, 55.06; H, 3.85. found: N, 3.51; C, 55.00; H, 3.95.

6-Bromo-3-ethoxymethyl-2-(4-bromophenyl)imino-2H-chromene (E₂₁): (1.35 g, 62%); m.p.: 129˜431° C., R_(f)=0.500 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.47 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.92 (dd, J=8.8, 2.0 Hz, 1H, ArH), 7.05 (dt, J=8.4, 3.2 Hz, 2H, RC═NArH), 7.34 (t, J=1.6 Hz, 1H, ArCH═C), 7.40 (dd, J=8.8, 2.4, 1H, ArH), 7.44-7.51 (m, 2H, RC═NArH), 7.55 (dd, J=9.2, 2.0 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.22, 66.87, 67.33, 116.27, 117.07, 121.63, 124.69, 128.86, 129.60, 130.59, 131.70, 132.47, 132.60, 144.68, 147.67, 151.05; IR (KBr cm⁻¹): 2971, 2866, 2362, 1644, 1476, 1382, 1180, 1122, 1064, 903, 827; EI-MS (70 eV) m/z: 438 ([M+2]⁺, 0.31%), 434 (M⁺, 0.01%), 408 (61%), 396 (47%), 394 (96%), 392 (66%), 312 (100%), 311 (51%), 310 (58%); Anal. calcd for C₁₈H₁₅Br₂NO₂: N, 3.46; C, 49.46; H, 3.46. found: N, 3.15; C, 48.40; H, 3.40.

6-Bromo-3-ethoxymethyl-2-(4-methylphenyl)imino-2H-chromene (E₂₂): (1.22 g, 66%); m.p.: 116˜117° C., R_(f)=0.500 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.32 (t, J=7.2 Hz, 3H, CH₂OCH₂CH₃), 2.35 (s, 3H, RC═NArCH₃), 3.69 (q, J=6.8 Hz, 2H, CH₂OCH₂CH₃), 4.48 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.91 (d, J=8.8 Hz, 1H, ArH), 7.10-716 (m, 4H, RC═NArH) 7.27 (t, J=1.6 Hz, 1H, ArCH═C), 7.36 (dd, J=8.8, 2.4 Hz, 1H, ArH), 7.44 (d, J=2.0 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.23, 20.99, 66.79, 67.46, 76.68, 117.04, 121.77, 122.94, 127.96, 129.23, 129.42, 130.96, 132.14, 133.60, 142.83, 146.79, 151.24; IR (KBr cm⁻¹) 2971, 2874, 2362, 1652, 1592, 1507, 1222, 1182, 1120, 1063, 908, 814; EI-MS (70 eV) m/z: 373 ([M+2]⁺, 1.3%), 371 (M⁺, 1.3%), 344 (87%), 343 (87%), 330 (87%), 329 (45%), 328 (100%), 32% (36%), 326 (29%); Anal. calcd for C₁₉H₁₈BrNO₇: N, 3.76; C, 61.30; H, 4.87. found: N, 3.74; C, 61.18; H, 4.83.

6-Bromo-3-ethoxymethyl-2-(4-methoxyphenyl)imino-2H-chromene (E₂₃): (1.30 g, 67%); m.p.: 134˜135° C., R_(f)=0.309 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.32 (t, J=6.8 Hz, CH₂OCH₂CH₃), 3.69 (q, J=7.2 Hz, 2H, CH₂OCH₂CH₃), 3.82 (s, 3H, RC═NArOCH₃), 4.47 (d, J=2.0 Hz, 2H, CH₂OCH₂CH₃), 6.89 (dt, J=7.2, 2.0 Hz, 2H, RC═NArH), 6.94 (d, J=8.4 Hz, 1H, ArH), 7.22-7.26 (m, 3H, RC═NArH, ArCH═C), 7.37 (dd, J=8.4, 2.4 Hz, 1H ArH), 7.45 (d, J=2.0 Hz, 1H, ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.24, 55.40, 66.79, 67.50 113.84, 115.91, 116.99, 121.87, 124.72, 127.65, 129.43, 131.12, 132.10, 138.40, 146.39, 151.26, 156.46; IR (KBr cm⁻¹): 2976, 2869, 2365, 1642, 1593, 1505, 1413, 1382, 1241, 1178, 1126, 1060, 1025, 815; EI-MS (70 eV) m/z: 389 ([M+2]⁺, 0.5%), 387 (M⁺, 0.8%), 360 (33%), 358 (36%), 345 (60%), 344 (37%), 343 (100%), 331 (24%), 328 (27%); Anal. calcd for C₁₉H₁₈BrNO₃: N, 3.61; C, 58.78; H, 4.67. found: N, 3.61; C, 58.70; H, 4.65.

6-Bromo-3-ethoxymethyl-2-(3-methoxyphenyl)imino-2H-chromene (E₂₄): (1.23 g, 65%); m.p.: 93˜94° C., R_(f)=0.35 7 (ethyl acetate:n-hexane=1:7); ¹H-NMR (CDCl₃, 400 MHz) δ/ppm: 1.33 (t, J=6.8 Hz, 3H, CH₂OCH₂CH₃), 3.70 (q, J=7.2 Hz, 2H, CH₂OCH₂CH₃), 3.81 (s, 3H, RC═NArOCH₃), 4.84 (d, J=1.6 Hz, 2H, CH₂OCH₂CH₃), 6.68 (dt, J=8.4, 0.8 Hz, 1H, RC═NArH), 6.72 (t, J=2.0 Hz, 1H, RC═NArH), 6.77 (dt, J=8.0, 0.8 Hz, 1H, RC═NArH), 6.92 (d, J=8.8 Hz, 1H, ArH), 7.25 (t, J=8.0 Hz, 1H, RC═NArH), 7.31 (t, J=1.6 Hz, 1H, ArCH═C), 7.37 (dd, J=8.8, 2.4 Hz 1H ArH), 7.47 (d, J=2.4 Hz 1H ArH); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.22, 55.20, 66, 82, 67.39, 108.32, 109.85, 115.19, 116.03, 117.14, 121.66, 128.345, 129.48, 130.72, 132.27, 146.93, 151.19, 160.00; IR (KBr cm⁻¹): 2970, 2361, 1648, 1584, 1477, 1268, 1232, 1182, 1121, 1065, 904, 807, 783; EI-MS (70 eV) m/z: 389 ([M+2]⁺, 0.4%), 387 (M⁺, 0.6%), 360 (44%), 359 (11%), 358.5 (44%), 346 (62%), 345 (47%), 344 (100%), 342 (25%); Anal. calcd for C₁₉H₁₈BrNO₃: N, 3.61; C, 58.78; H, 4.67. found: N, 3.61; C, 58.80; H, 4.70.

7-Benzyloxy-3-ethoxymethyl-(Z)-2-phenylimino-2H-chromene (E₂₅): (1.19 g, 62%); m.p.: 94-95° C., R_(f)=0.40 (ethyl acetate:n-hexane=1:9); IR (KBr cm⁻¹): 2973, 2867, 1649, 1612, 1505, 1385, 1262, 1164, 1130, 1065, 695; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.32 (3H, t, J=6.8 Hz, OCH₂CH₃), 3.70 (2H, q, J=6.8, Hz, OCH₂CH₃), 4.48 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 4.99 (2H, s, OCH₂Ph), 6.64 (1H, d, J=2.4 Hz, H-8), 6.76 (1H, dd, J=8.4, 2.4 Hz, H-6), 7.10 (1H, t, J=7.6 Hz, ArH), 7.17 (2H, d, J=7.6 Hz, ArH), 7.22 (1H, d, J=8.4 Hz, H-5), 7.30-7.39 (8H, m, H-4 and ArH); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.3, 66.7, 67.5, 70.2, 101.2, 111.6, 113.6, 122.8, 123.5, 126.2, 127.5, 127.9, 128.1, 128.6, 128.6, 129.9, 136.1, 146.3, 148.1, 153.6, 160.3; MS (EI): 385 (M⁺, 0.2%), 250 (42%), 91 (100%); Anal. calcd for C₂₅H₂₃NO₃ (385.46): C, 77.90; H, 6.01; N, 3.63. found: C, 77.94; H, 6.00; N, 3.60.

7-Methoxy-3-ethoxymethyl-(Z)-2-phenylimino-2H-chromene (E₂₆): (0.87 g, 57%); mp 107-108° C., R_(f)=0.40 (ethyl acetate:n-hexane=1:9); IR (KBr cm⁻¹): 2973, 2868, 1649, 1610, 1508, 1486, 1445, 1389, 1264, 1159, 1131, 1064, 759; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.33 (3H, t, J=6.8 Hz, OCH₂CH₃), 3.71 (2H, q, J=6.8, Hz, OCH₂CH₃), 3.77 (3H, OCH₃), 4.48 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 6.55 (1H, J=2.4 Hz, H-8), 6.69 (1H, dd, J=8.4, 2.4, H-6), 7.10 (1H, tt, J=7.6, 1.2 Hz, ArH), 7.16-7.19 (2H, m, ArH), 7.23 (1H, d, J=8.4 Hz, H-5), 7.33-7.37 (2H, m, ArH), 7.34 (1H, t, J=1.6 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.3, 55.6, 66.7, 67.5, 100.1, 111.1, 113.3, 122.8, 123.5, 126.0, 127.9, 128.6, 129.9, 146.3, 148.2, 153.7, 161.2; MS (EI): 309 (M⁺, 0.5%), 280 (100%) 265 (94%), 264 (72%), 252 (60%); Anal. calcd for C₁₉H₁₉NO₃ (309.36): C, 73.77; H, 6.19; N, 4.53. found: C, 73.87, H, 6.09; N, 11.46.

8-Methoxy-3-ethoxymethyl-(Z)-2-phenylimino-2H-chromene (E₂₇): (1.04 g, 67%); m.p.: 88-90° C., R_(f)=0.43 (ethyl acetate:n-hexane=1:9); IR (KBr cm⁻¹): 2972, 2866, 1645, 1586, 1482, 1269, 1224, 1183, 1106, 1062, 765; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.34 (3H, t, J=6.8 Hz, OCH₂CH₃), 3.72 (2H, q, J=6.8, Hz, OCH₂CH₃), 3.81 (3H, s, OCH₃), 4.52 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 6.90 and 6.95 (each 1H, dd, J=8.0, 1.6 Hz, H-5 and H-7), 7.05 (1H, t, J=8.0 Hz, H-6), 7.11 (1H, tt, J=7.2, 1.2 Hz, ArH), 7.33-7.37 (2H, m, ArH), 7.37 (1H, t, J=1.6 Hz, H-4), 7.41-7.44 (2H, m, ArH); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.3, 56.6, 66.8, 67.6, 113.1, 119.2, 120.7, 123.4, 124.0, 124.1, 128.5, 129.6, 129.7, 142.1, 145.5, 146.9, 147.4; MS (EI): 309 (M⁺, 0.5%), 280 (100%), 265 (95%), 264 (70%); Anal. calcd. For Cl₁₉H₁₉NO₃ (309.36): C, 73.77; H, 6.19; N, 4.53. found: C, 73.79; H, 6.21; N, 4.50.

Examples 28-36 Preparation of the Coumarin Compounds [(F₁)˜(F₉)]

Each of the coumarin compounds (F₁)˜(F₉) was prepared according to scheme III below by: dissolving 1.0 mmol of a corresponding one of the chromene compounds (E₁){grave over ( )}(E₂){grave over ( )}(E₉){grave over ( )}(E₁₀){grave over ( )}(E₁₁){grave over ( )}(E₁₈){grave over ( )}(E₂₅){grave over ( )}(E₂₆) and (E₂₇) into 10 mL of THF to form a coumarin solution, and adding 5 mL, 15 wt % of HCl aqueous solution into the coumarin solution at 0° C. to form a reaction solution, followed by raising the reaction solution from 0° C. to room temperature under a nitrogen gas for 30 mins.

The reaction solution was mixed with a saturated NaCl aqueous solution after the reaction was completed. The reaction product in the reaction solution was subsequently extracted using CH₂Cl₂, and was cleaned with a saturated NaHCO₃ aqueous solution, dried, filtered, and concentrated, so as to obtain a colorless crystal of a coumarin compound of formula (F).

Structure Identification of the Coumarin Compounds [(F₁)˜(F₉)]

3-Methoxymethylcoumarin (F₁): (0.13 g, 68); m.p.: 72-73° C., R_(f)=0.33 (ethyl acetate:n-hexane=1.5)); IR (KBr cm⁻¹): 2957, 2919, 1713, 1603, 1454, 1394, 1168, 1115, 1043, 1010, 925, 780, 630; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 3.52 (3H, s, CH₂OCH₃), 4.41 (2H, d, J=1.6 Hz, CH₂OCH₃), 7.28 (1H, td, J=7.6, 0.8 Hz, ArH), 7.34 (1H, d, J=8.4 Hz, ArH), 7.48-7.53 (2H, m, ArH), 7.78 (1H, t, J=1.6 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 59.1, 69.0, 116.5, 119.2, 124.5, 126.0, 127.7, 131.1, 138.2, 153.1, 160.4; MS (EI) m/z: 190 (M⁺, 2%), 175 (68%), 160 (100%), 103 (41%); Anal. calcd for C₁₁H₁₀O₃ (190.20): C, 69.46; H, 5.30. found: C, 69.21; H, 5.42.

3-Ethoxymethylcoumarin (F₂): (0.15 g, 73%); m.p.: 95-96° C., R_(f)=0.38 (ethyl acetate:n-Hexane=1:5); IR (KBr cm⁻¹): 2970, 2924, 2863, 2341, 1717, 1605, 1574, 1447, 1384, 1283, 1172, 1116, 1061, 919, 756, 630; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.31 (3H, t, J=7.0 Hz, OCH₂CH₃), 3.68 (2H, q, J=7.0 Hz, OCH₂CH₃), 4.46 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 7.28 (1H, td, J=7.6, 1.2 Hz, ArH), 7.34 (1H, d, J=8.0 Hz, ArH), 7.48-7.52 (2H, ArH), 7.81 (1H, t, J=1.6 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.2, 66.9, 66.9, 116.5, 119.2, 124.4, 126.4, 127.7, 131.0, 138.1, 153.1, 160.5; MS (EI) m/z: 175 ([M-(C₂H₅)]⁺, 53%), 160 (100%), 132 (51%), 131 (42%); Anal. calcd for C₁₂H₁₂O₃ (204.22): C, 70.57; H, 5.92. found: C, 70.60; H, 5.95.

3-Isopropoxymethylcoumarin (F₃): (0.16 g, 73%); R_(f)=0.46 (ethyl acetate:n-hexane=1:5), m.p.: 72-71° C., IR (KBr cm⁻¹): 2970, 1715, 1602, 1449, 1169, 1125, 1036, 917, 754, 630; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.27 (6H, d, J=6.4 Hz, OCH(CH₃)₂), 3.78 (1H, hept, J=6.4 Hz, OCH(CH₃)₂), 4.45 (2H, d, J=1.6 Hz, CH₂OCH(CH₃)₂), 7.27 (1H, td, J=7.6, 0.8 Hz, ArH), 7.33 (1H, d, J=8.0 Hz, ArH), 7.47-7.52 (2H, m, ArH), 7.82 (1H, t, J=1.6 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 22.1, 64.5, 72.4, 116.5, 119.3, 124.4, 127.0, 127.7, 130.9, 137.9, 153.0, 160.5; MS (EI) m/z: 175 ([M-(C₃H₇)]⁺, 52%), 160 (100%), 159 (49%), 132 (45%); Anal. calcd for C₁₃H₁₄O₃ (218.25): C, 71.54; H, 6.47. found: C, 71.51; H, 6.45.

3-Butoxymethylcoumarin (F₄): (0.18 g, 77%); m.p.: 69-70° C., R_(f)=0.49, (ethyl acetate:n-hexane=1:5); IR (KBr cm⁻¹): 2924, 2854, 1717, 1637, 1456, 1385, 1282, 1170, 1144, 1114, 1055, 1018, 919, 756, 631; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 0.96 (3H, t, J=7.4 Hz, OCH₂CH₂CH₂CH₃), 1.40-1.49 (2H, m, OCH₂CH₂CH₂CH₃), 1.63-1.70 (2H, m, OCH₂CH₂CH₂CH₃), 3.61 (2H, t, J=6.6 Hz, OCH₂CH₂CH₂CH₃), 4.45 (2H, d, J=1.6 Hz, CH₂OC₄H₉), 7.28 (1H, td, J=7.2, 0.8 Hz, ArH), 7.34 (1H, H, J=8.0 Hz, ArH), 7.47-7.52 (2H, m, ArH), 7.79 (1H, br s, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 13.9, 19.3, 31.7, 67.1, 71.3, 116.5, 119.3, 124.4, 126.5, 127.7, 131.0, 138.0, 153.0, 160.5; MS (EI) m/z: 175 ([M-(C₄H₉)]⁺, 37%), 160 (100%), 132 (53%); Anal. calcd for C₁₄H₁₆O₃ (232.28): C, 72.39; H, 6.94. found: C, 72.35; H, 6.95.

6-Chloro-3-ethoxymethylcoumarin (F₅): (0.18 g, 75%); R_(f)=0.45 (ethyl acetate:n-hexane=1:5), m.p.: 100-101° C.; IR (KBr cm⁻¹); 2972, 2861, 1729, 1637, 1605, 1570, 1478, 1379, 1266, 1172, 1124, 1055, 1014, 925, 826, 758, 659; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.31 (3H, t, J=7.0 Hz, OCH₂CH₃), 3.68 (2H, q, J=7.0 Hz, OCH₂CH₃), 4.45 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 7.28 (1H, d, J=8.8 Hz, H-8), 7.45 (2H, dd, J=8.8, 2.4 Hz, H-7), 7.50 (1H, d, J=2.4 Hz, H-5), 7.74 (1H, brs, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.1, 66.8, 66.9, 117.9, 120.3, 126.9, 127.9, 129.7, 130.9, 136.7, 151.4, 159.8; MS (EI) m/z: 211 ([(M+2)-(C₂H₅)]⁺, 14%), 209 ([M-(C₂H)]⁺, 45%), 194 (100%), 166 (54%), 165 (41%); Anal. calcd for C₁₂H₁₁ClO₃ (238.67): C, 60.39; H, 4.65. found: C, 60.21; H, 4.64.

6-Bromo-3-ethoxymethylcoumarin (F₆): (0.20 g, 71%); m.p.: 118-119° C., R_(f)=0.48 (ethyl acetate:n-hexane=1:5); IR (KBr cm⁻¹): 2970, 2860, 1728, 1637, 1601, 1476, 1379, 1266, 1246, 1173, 1125, 1054, 1013, 923, 824, 759, 650; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.31 (3H, t, J=7.0 Hz, OCH₂CH₃), 3.67 (2H, q, J=7.0 Hz, OCH₂CH₃), 4.45 (2H, d, J=1.6 Hz, CH₂OCH₂CH), 7.22 (1H, d, J=8.8 Hz, H-8), 7.58 (1H, dd, J=8.8, 2.4 Hz, H-7), 7.65 (1H, d, J=2.4 Hz, H-5), 7.73 (1H, t, J=1.6 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.1, 66.8, 66.9, 117.0, 118.3, 120.8, 127.8, 130.0, 133.7, 136.6, 151.9, 159.8; MS (EI) m/z: 255 ([(M+2)-(C₂H₅)]⁺, 34%), 253 ([M-(C₂H₅)]⁺, 39%), 240 (95%), 239 (22%), 238 (100%), 212 (36%), 211 (33%), 210 (36%), 102 (63%); Anal. calcd for C₁₂H₁₁BrO₃ (283.12): C, 50.91; H, 3.92. found: C, 50.82; H, 3.92.

7-Benzyloxy-3-ethoxymethylcoumarin (F₇): (0.27 g, 87%); m.p.: 122-124° C., R_(f)=0.48 (ethyl acetate:n-hexane=1:6); IR (KBr cm⁻¹): 2976, 2923, 2858, 1714, 1620, 1388, 1245, 1163, 1132, 843, 724; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.30 (3H, t, J=6.8 Hz, OCH₂CH₃), 3.66 (2H, q, J=6.8 Hz, OCH₂CH₃), 4.42 (2H, d, J=1.2 Hz, CH₂OCH₂CH₃), 5.11 (2H, s, OCH₂Ph), 6.88 (1H, d, J=2.4 Hz, H-8), 6.92 (1H, dd, J=8.8, 2.4 Hz, H-6), 7.33-7.45 (6H, m, H-5 and ArH), 7.73 (1H, br s, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.1, 66.7, 66.9, 70.4, 101.6, 113.0, 113.2, 122.8, 127.5, 128.3, 128.6, 128.7, 135.8, 138.5, 154.7, 160.8, 161.3; MS (EI) m/z: 310 (M⁺, 0.4%), 91 (100%); Anal. calcd. for C₁₉H₁₉O₄ (310.34): C, 73.53; H, 5.85. found: C, 73.49; H, 5.87.

7-Methoxy-3-ethoxymethyl-coumarin (F₈): (0.19 g, 81%); m.p.: 64-66° C., R_(f)=0.58 (ethyl acetate:n-hexane=1:3); IR (KBr cm⁻¹): 2975, 2909, 2874, 1726, 1624, 1390, 1151, 1121, 1022, 926, 823; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.30 (3H, t, J=6.8 Hz, OCH₂CH₃), 3.67 (2H, q, J=6.8 Hz, OCH₂CH₃), 3.87 (3H, s, OCH₃), 4.43 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 6.83 (1H, d, J=2.8 Hz, H-8), 6.85 (1H, dd, J=8.4, 2.8 Hz, H-6), 7.40 (1H, d, J=8.4 Hz, H-5) 7.74 (1H, t, J=1.6 Hz, H-4); ¹³C-NMR (100 MHz, CDCl₃) δ/ppm: 15.2, 55.7, 66.7, 67.0, 100.5, 112.6, 112.9, 122.7, 128.6, 138.6, 154.8, 160.9, 162.2; MS (EI) m/z: 234 (M⁺, 1%), 205 ([M-(C₂H₅)]⁺, 30%), 190 (100%), 162 (69%); Anal. calcd. for C₁₃H₁₄O₄ (234.25): C, 66.66; H, 6.02. found: C, 66.54; H, 6.00.

8-Methoxy-3-ethoxymethyl-coumarin (F₉): (0.20 g, 85%); m.p.: 131-133° C., R_(f)=0.51 (ethyl acetate:n-hexane=1:3); IR (KBr cm⁻¹): 2974, 2862, 1698, 1607, 1580, 1481, 1456, 1279, 1268, 1177, 1124, 1103, 1066, 914, 744; ¹H-NMR (400 MHz, CDCl₃) δ/ppm: 1.31 (3H, t, J=6.8 Hz, OCH₂CH₃), 3.68 (2H, q, J=6.8 Hz, OCH₂CH₃), 3.97 (3H, s, OCH₃), 4.46 (2H, d, J=1.6 Hz, CH₂OCH₂CH₃), 7.05 and 7.09 (each 1H, dd, J=8.0, 1.2 Hz, H-5 and H-7), 7.21 (1H, t, J=8.0 Hz, H-6), 7.78 (1H, J=1.6 Hz, H-4); ¹³C-NMR (CDCl₃, 100 MHz) δ/ppm: 15.1, 56.2, 66.9, 112.9, 119.2, 119.9, 124.3, 126.7, 138.1, 142.7, 147.1, 159.9; MS (EI) m/z: 234 (M⁺, 0.3%), 205 ([M-(C₂H₅)]⁺, 31%), 190 (100%), 162 (39%); Anal. calcd. for C₁₃H₁₄O₄ (234.25): C, 66.66; H, 6.02. found: C, 66.61; H, 5.99.

While the present invention has been described in connection with what are considered the most practical and preferred embodiments, it is understood that this invention is not limited to the disclosed embodiments but is intended to cover various arrangements included within the spirit and scope of the broadest interpretation and equivalent arrangements. 

1. A method for preparing a coumarin compound of formula (F), in which R¹, R², and R³ are independently H, C₁˜C₇ alkoxy, C₁˜C₇ alkyl, phenoxy, benzyloxy, or a halogen atom; R⁴ is an alkyl group; and Ar is an optionally substituted aryl group,

the method comprising: treating a chromene compound having the following formula (E)

with an acid in the presence of water.
 2. The method of claim 1, wherein R⁴ is a C₁-C₄ alkyl group.
 3. The method of claim 1, wherein Ar is unsubstituted aryl, haloaryl, alkylaryl, or alkoxyaryl.
 4. The method of claim 3, wherein Ar is phenyl, halophenyl, alkoxyphenyl, or alkylphenyl.
 5. The method of claim 4, wherein Ar is phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl or 3-methoxy-phenyl.
 6. The method of claim 2, wherein R¹, R², and R³ are independently H, Cl, Br, benzyloxy, or methoxy; and R⁴ is methyl, ethyl, i-propyl, or n-butyl.
 7. The method of claim 1, wherein the acid is selected from the group consisting of HCl, HBr, HI, CH₃CO₂H, and combinations thereof. 